The present invention, in some embodiments thereof, relates to Pigment epithelium-derived factor (PEDF) and uses of same in the treatment of uterine fibroids.
Uterine fibroids (leiomyomas) are the most common benign tumors in women. Fibroids disrupt the function of the uterus and cause excessive uterine bleeding, anemia, infertility, defective implantation of embryos, recurrent pregnancy loss, preterm labor, obstruction of labor, pelvic discomfort and urinary incontinence; in fact, uterine fibroids may mimic or mask malignant tumors. Approximately 200,000 hysterectomies, 30,000 myomectomies, and thousands of selective uterine-artery embolizations and high-intensity focused ultrasound procedures are performed annually in the United States to remove uterine fibroids. The annual economic burden of these tumors is estimated to be between 5.9 and 34.4 billion US $.
Uterine fibroids arise from the uterine smooth-muscle tissue (i.e., the myometrium). Histologically, fibroids are benign neoplasms composed of disordered smooth-muscle cells buried in abundant quantities of extracellular matrix. A striking feature of uterine fibroids is their dependency on the ovarian steroids estrogen and progesterone. Ovarian activity is essential for fibroid growth; most fibroids shrink after menopause. Gonadotropin-releasing-hormone (GnRH) analogues, which suppress ovarian activity and reduce circulating levels of estrogen and progesterone, shrink fibroids and reduce associated uterine bleeding.
Fibroids comprise a unique vascular architecture that consists of an avascular core surrounded by a well-vascularized myometrium caused, most likely, due to an angiogenic imbalance. Researchers suggest that the preliminary tumor, which is small in size with a minimal intrinsic blood supply, may release angiogenic factors as vascular endothelial growth factor (VEGF) that lead to an increase in the vascular density of the surrounding myometrium. This may, in turn, give rise to capillary sprouts that vascularize the small fibroid, promoting its growth and enlargement. This increase in vascular density of myometrium may account for the symptoms of menorrhagia observed in women with fibroids.
Pigment epithelium-derived factor (PEDF) is a non-inhibitory member of the serine protease inhibitors (serpin) superfamily, which was first described as a neurotrophic factor, able to promote and support the growth of neuronal cells. It was later found that on top of having neurotrophic activity, PEDF has an anti-angiogenic, anti-inflammatory and anti-oxidative properties. To date, two distinct PEDF receptors were proposed: an 80 kDa PEDF putative receptor (PEDF-RN; PNPLA2) involved in PEDF neuroprotecting, pro-survival functions; and a 60 kDa PEDF putative receptor (PEDF-RA; Laminin receptor) involved in PEDF pro-apoptotic, anti-angiogenic activities [Manalo et al. Expert Opin Ther Pat (2011): 21, 121-130; and Yamagishi et al. Cell Tissue Res (2005) 320: 437-445].
Although originally discovered in culture media of retinal pigment epithelial cells, PEDF is widely expressed throughout the body: the nervous system, ovary, uterine, liver and plasma. Despite the significant expression of PEDF in the reproductive system, there is only limited data about its function in the ovary and uterus [Cheung et al., Endocrinology, 2006. 147(9): p. 4179-91; Chuderland et al. J Clin Endocrinol Metab (2013) 98: E258-266; and Chuderland et al. Mol Hum Reprod (2013) 19: 72-81; Pollina et al., Cell Cycle, 2008. 7(13): p. 2056-70; Palmieri et al. Exp Cell Res, 1999. 247(1): p. 142-7.]. Previous work has suggested using PEDF in the treatment of tumors [Manalo et al. Expert Opin Ther Pat (2011): 21, 121-130] as well as in endometriosis (US20130053312).
Additional Related Background Art:    U.S. Patent Publication Number US20030216286;    U.S. Patent Publication Number US20070087967;    U.S. Patent Publication Number US20040071659;    U.S. Patent Publication Number US20090118191;    Nelius et al. [J Clin Oncol 31, 2013 (suppl 6; abstr 173)];    Ma and Waxman [Mol Cancer Ther. (2008) 7(12): 3670-3684];    Jia and Waxman [Cancer Lett. (2013) 330(2):241-9];    Chuderland et al. 2014 Mol. Cell. Endocrinol. 390:85-92;    Folkman et al. Nat. Rev. 6:273-286 (2007).